Dean Wong

Imaging opiate receptors in the human brain by positron tomography

Carfentanil is a potent, synthetic opiate that binds to mu opiate receptors with very high affinity (K1 = 0.051 n M, 37°). In rat brain, carfentanil is 90 and 250 times more selective for mu opiate receptors compared with delta and kappa opiate receptors, respectively. Carbon-11-carfentanil was synthesized by reacting [11C]methyliodide with the carboxylic acid precursor of carfentanil. Carbon-11-carfentanil was injected intravenously in man and a baboon and the distribution of the radioactivity in the brain was monitored using positron emission tomography. High concentrations of radioactivity were observed in the basal ganglia and thalamus, intermediate concentrations in the frontal and parietal cerebral cortex, and low concentrations in the cerebellum and occipital cortex; this distribution corresponds to the known regional density of opiate receptors measured using in vitro techniques. This heterogeneous distribution could be abolished by pretreatment with naloxone (1 mg/kg), an opiate antagonist. The percent inhibition of binding by naloxone is approximately 90% in the caudate nucleus and medial thalamus for the period 30–60 min after injection; therefore, this method is associated with a high level of specific binding to opiate receptors compared with nonspecific binding sites. The ability to measure opiate receptors in vivo in man makes it possible to study a variety of neurologic and psychiatric disorders in which opiate receptors are thought to be abnormal and to study physiologic role of opiate receptors in the central nervous system.

Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [11C]PiB

Objective: To investigate whether longitudinal declines in cognition are associated with higher fibrillar amyloid-beta (Aβ) deposition in vivo in individuals without dementia. Method: [11C]PiB images were obtained to measure fibrillar Aβ burden in 57 participants without dementia from the Baltimore Longitudinal Study of Aging. Participants (33 men, 24 women) had a mean (SD) age of 78.7 (6.2) years. Six participants (4 men, 2 women) had mild cognitive impairment defined as Clinical Dementia Rating = 0.5. To measure [11C]PiB retention, distribution volume ratios (DVR) for 15 regions of interest were estimated by fitting a simplified reference tissue model to the measured time activity curves. Mixed effects regression was used to predict cognitive trajectories over time using data before and including time of PiB (mean follow-up 10.8 years), with mean cortical DVR, age at baseline, sex, and education as independent predictors. Voxel-based analysis identified local associations. Results: [11C]PiB retention was higher in older individuals. Greater declines over time in mental status and verbal learning and memory, but not visual memory, were associated significantly with higher PiB retention. Voxel-based analysis showed significant associations in frontal and lateral temporal regions. Conclusions: Higher Aβ deposition is associated with greater longitudinal decline in mental status and verbal memory in the preceding years. The differential association for verbal but not visual memory may reflect the greater reliance of verbal word list learning on prefrontal regions, which show early Aβ deposition. Prospective imaging may help distinguish between individuals with evolving neuropathology who develop accelerated cognitive decline vs those with normal aging.

Neuropsychological and neuroradiological correlates in Huntington's disease.

Measurements of cortical and subcortical atrophy were made on CT scans of 34 patients with Huntingtons disease. Significant correlations were found between the bicaudate ratio (BCR) and an eye movement scale (r = 0.44, p less than 0.01), and activities of daily living scale (r = 0.57, p less than 0.001) and the Mini-Mental State Exam (r = 0.49, p less than 0.01). No correlations were found between BCR values and severity of chorea or voluntary motor impairment. A detailed neuropsychological evaluation of 18 Huntingtons disease patients showed significant correlations between the BCR and Symbol Digit Modalities test (r = 0.65, p less than 0.01), and parts A (r = 0.72, p less than 0.001) and B (r = 0.80, p less than 0.0001) of the Trail Making Test. These data support work in primates that demonstrates the role of the caudate nucleus in cognitive and oculomotor functions, but not in motor control (which is governed by putamino-subthalamic systems). The specific cognitive skills correlated with caudate atrophy in Huntingtons disease are those reported in primate work to be served by the frontal-caudate loop system: eye movements, conceptual tracking, set shifting and psychomotor speed.

The second generation HRRT - a multi-centre scanner performance investigation

The high resolution research tomograph (HRRT) is one of the most complex existing positron emission tomographs: it is the only human size scanner capable of decoding the depth of the /spl gamma/-ray interaction in the crystal, using a lutetium LSO/LYSO phoswich detector arrangement. In this study we determined basic scanner hardware characteristics, such as scanner data acquisition stability, and their variability across eleven centres. In addition a subset of the NEMA NU-2001 standards measurements was performed. We found (i) significant variability in the DOI decoding results between centres, (ii) a trend toward an increasing number of detected true coincident events as a function of elapsed time from scanner calibration likely due to a shifting energy spectrum, (iii) a count-rate dependent layer identification, (iv) scatter fraction ranging from /spl sim/ 42% to 54% where the variability was partly related to the shifting of the energy spectrum, (v) sensitivity ranging from /spl sim/5.5% to 6.5% across centres, (vi) resolution of /spl sim/(2.5 mm)/sup 3/, fairly consistent across centres, (vii) image quality which is very comparable to other scanners.

Neuroimaging studies in Rett syndrome

Neuroimaging is a key instrument for determining structural and in vivo functional status of the brain, non-invasively. Multiple approaches can now determine aspects of anatomic and neurochemical changes in brain, and have been utilized effectively in Rett Syndrome patients to understand the biological basis of this neurodevelopmental disorder. Studies performed at our institute include volumetric analyses of MRI, magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), cerebral blood flow measurements with MRI, and positron emission tomography scans (PET). These studies have provided considerable insight into mechanisms underlying the clinical features of this disease. Volumetric analyses suggest that decreased brain volume in RS results from global reductions in both gray and white matter of the brain. A selective vulnerability of the frontal lobes is evidenced by the preferential reduction of blood flow, increased choline and reduced n-acetyl aspartate (NAA) by MRS, and increased glucose uptake in these same regions as shown by ((18)F)-fluorodeoxyglucose (FDG) PET scans. We hypothesize that the increased glucose uptake relates to increased glutamate cycling in synapses. The resulting neuroexcitotoxic injury to the developing brain contributes to the seizures, behavioral disturbance and respiratory irregularities commonly seen in phases 1 and 2 of this disorder.

In vivo specific binding of [3H] 1-nicotine in the mouse brain

[3H] 1-Nicotine was used as a receptor ligand in the intact mouse. It was injected i.v., and radioactivity in brain regions was assayed. Nonspecific binding was estimated by pretreatment with unlabelled 1-nicotine. Radioactivity entered the brain rapidly, was heterogeneously distributed, and declined after 5 min. Estimated specific binding was highest in the medial and posterior cortex, midbrain, thalamus/hypothalamus and medulla/pons; intermediate in the cerebellum, caudate/putamen, frontal and frontoparietal cortex; and lowest in the hippocampus and olfactory bulb. Autoradiography showed similar patterns. Coinjection of unlabelled 1-nicotine reduced specific binding so that it approached estimated nonspecific binding. Nicotinic agonists reduced radioactivity in the thalamus/hypothalamus, but nicotinic antagonists were less active. Non-nicotinic drugs did not reduce brain radioactivity. The results suggest that radiolabelled nicotine may be used for in vivo receptor studies despite problems in estimating nonspecific binding.

Striatal dopamine D2 receptor quantification and superior temporal gyrus: Volume determination in 14 chronic schizophrenic subjects

Chronic schizophrenic (n = 14) and normal subjects (n = 15) were studied with resonance imaging (MRI) and positron emission tomography (PET). Two PET scans were carried out to estimate caudate dopamine D2 receptor densities. MRI was used to measure the volume of the superior temporal gyrus. Average striatal D2 receptor density (Bmax) was significantly higher in the schizophrenic group than in the normal group. Average left superior temporal gyral volume was significantly smaller in the schizophrenic group than in the normal group, and the same tendency was found for the right superior temporal gyrus. Thus, the main finding of this combined analysis of functional and structural neuroimaging techniques was an inverse relationship between reduced superior temporal gyral volume and elevated striatal D2 receptor Bmax values. These preliminary findings require confirmation in larger groups of patients and control subjects.

Artifacts in camera based single photon emission tomography due to time activity variation

Image quality in single photon emission computed tomography (SPECT) using a rotating gamma camera is dependent on the time course of the tracer in the field of view. If acquisition times are slow comapred to the tracer turnover, artifacts may occur in the reconstructed images. The properties of such artifacts were studied by computer simulation. Experimental projection data of point sources, cylindrical phantoms, and an anatomically realistic brain phantom were altered by sequentially weighting the projections with a function that varied exponentially or linearly with time. The observed distortion in the reconstructed images could be related to the ratio between the object activity variation and the camera rotation time. If the tracer concentration changed less than a factor of two during one camera rotation then little image distortion was visible although quantitatively the resolution was degraded.If the objects activity variation with time is fast enough to produce noticeable distortion, the artifacts can be reduced by performing multiple, rapid, camera rotations, instead of one rotation, for the same total acquisition time. The proposed procedure is computer storage space intensive and takes longer to produce the transaxial images, but improves image quality.

Dopamine transporter imaging with novel, selective cocaine analogs

RTI-121 and RTI-122 are 3 beta-substituted phenyltropane analogs of cocaine that have high, selective binding affinity for dopamine transporters. [123I]RTI-121 and [123I]RTI-122 bind to dopamine transporters in vivo after intravenous administration and permit imaging of the transporters.

Dopamine transporter changes in neuropsychiatric disorders.

Publisher Summary The highest concentrations of dopamine transporters (DATs) are found in the basal ganglia, corresponding to the amount of dopamine (DA) nerve terminals in this brain region. Numerous studies demonstrating parallel losses of DA levels and DAT after lesions of nigrostriatal DA neurons suggest that the density of DAT is an excellent marker of the structural integrity of the dopaminergic system. In vivo imaging of DAT has been performed mainly in patients with Parkinsons disease to demonstrate the marked loss of nigrostriatal DA nerve terminals in this disorder. However, positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of DAT have been shown to be useful in various other neurodegenerative disorders, including Lesch-Nyhan disease (LND), Rett syndrome, Tourettes syndrome, stimulant abuse, and progressive supranuclear palsy. A marked reduction of striatal DAT densities has been reported in methamphetamine treated animals. In baboon studies with methamphetamine treatment, a dose-related reduction in DAT densities occurs. These studies are followed by postmortem analysis of neurochemical parameters. In recent years, the synthetic amphetamine analogue methcathinone (2-methylamino-1-phenylpropanone, ephedrone, “Cat”) has emerged as a recreational drug of abuse. In animals, methcathinone, like methamphetamine, produces toxic effects on brain DA and serotonin neurons. Moreover, studies in human subjects with a history of methcathinone abuse suggest a DAT decline as well.